US20170209402A1 - Carboxy-cyclopropyl undecanol compounds for treatment of liver disease and other medical disorders - Google Patents

Carboxy-cyclopropyl undecanol compounds for treatment of liver disease and other medical disorders Download PDF

Info

Publication number
US20170209402A1
US20170209402A1 US15/125,401 US201515125401A US2017209402A1 US 20170209402 A1 US20170209402 A1 US 20170209402A1 US 201515125401 A US201515125401 A US 201515125401A US 2017209402 A1 US2017209402 A1 US 2017209402A1
Authority
US
United States
Prior art keywords
liver
cyclopropyl
carboxy
compound
disorder
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US15/125,401
Other languages
English (en)
Inventor
Jeffrey C. Hanselman
Rai Ajit K. Srivastava
Roger S. Newton
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Esperion Therapeutics Inc
Original Assignee
Esperion Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Esperion Therapeutics Inc filed Critical Esperion Therapeutics Inc
Priority to US15/125,401 priority Critical patent/US20170209402A1/en
Assigned to ESPERION THERAPEUTICS, INC. reassignment ESPERION THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SRIVASTAVA, RAI AJIT K., NEWTON, ROGER S., HANSELMAN, JEFFREY C.
Assigned to ESPERION THERAPEUTICS, INC. reassignment ESPERION THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SRIVASTAVA, RAI AJIT K., NEWTON, ROGER S., HANSELMAN, JEFFREY C.
Publication of US20170209402A1 publication Critical patent/US20170209402A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the invention provides methods of using carboxy-cyclopropyl undecanol compounds and pharmaceutically acceptable salts thereof to treat liver disease and other medical disorders associated with elevated lipid levels in the liver.
  • Fatty liver disorders also known as fatty liver or fatty liver disease (FLD) relate to a condition where large vacuoles of triglyceride fat accumulate in liver cells.
  • FLD fatty liver or fatty liver disease
  • FLD may be categorized into two separate conditions: alcoholic FLD (also known as alcoholic steatosis; caused at least in part by alcohol abuse) and non-alcoholic FLD (NAFLD; not caused by alcohol abuse). Both conditions often show micro-vesicular and macro-vesicular fatty changes at different stages of the disease. Accumulation of fat may also be accompanied by a progressive inflammation of the liver (hepatitis), called steatohepatitis.
  • Steatohepatitis may be further specified as alcoholic steatohepatitis and non-alcoholic steatohepatitis (NASH).
  • Non-alcoholic fatty liver disease-associated cirrhosis is the most severe form of the disease and is typically characterized by liver inflammation that leads to scarring of liver tissue.
  • Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are common causes of chronic liver disease in the adult population and represent crucial risk factors for progression to liver cirrhosis, hepatocellular carcinoma, and liver failure.
  • the increased incidence of NAFLD and NASH may be linked to the increasing incidence of obesity in the United States. NASH can cause scarring and hardening of the liver, leading to cirrhosis and eventually to hepatocellular carcinoma and liver failure.
  • the invention provides methods of using carboxy-cyclopropyl undecanol compounds and pharmaceutically acceptable salts thereof to treat liver disease and other medical disorders associated with elevated lipid levels in the liver.
  • Particularly preferred embodiments provide methods of treating steatohepatitis, such as nonalcoholic steatohepatitis using the compound 1,11-bis-(1-carboxy-cyclopropyl)-undecan-6-ol or a pharmaceutically acceptable salt thereof.
  • the therapeutic methods provide benefits to both pediatric and adult patients that may suffer from medical disorders described herein, such as nonalcoholic steatohepatitis.
  • one aspect of the invention provides a method of treating a liver disorder selected from the group consisting of steatohepatitis, alcoholic liver disease, fatty liver, liver steatosis, liver cirrhosis, liver fibrosis, and acute fatty liver of pregnancy.
  • the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of 1,11-bis-(1-carboxy-cyclopropyl)-undecan-6-ol and a pharmaceutically acceptable salt thereof to treat the disorder.
  • Another aspect of the invention provides a method of treating a disorder selected from the group consisting of lipodystrophy, lysosomal acid lipase deficiency, and a glycogen storage disease.
  • the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of 1,11-bis-(1-carboxy-cyclopropyl)-undecan-6-ol and a pharmaceutically acceptable salt thereof to treat the disorder.
  • Yet another aspect of the invention provides a method of treating a disorder selected from the group consisting of hepatitis C, an infection by human immunodeficiency virus, an alpha 1-antitrypsin deficiency, Bassen-Kornzweig syndrome, hypobetalipoproteinemia, Celiac disease, Wilson disease, and Weber-Christian syndrome.
  • the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of 1,11-bis-(1-carboxy-cyclopropyl)-undecan-6-ol and a pharmaceutically acceptable salt thereof to treat the disorder.
  • Yet another aspect of the invention provides a method of treating a condition selected from the group consisting of toxic liver injury, total parenteral nutrition, severe surgical weight loss, environmental toxicity, malnutrition, and starvation.
  • the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of 1,11-bis-(1-carboxy-cyclopropyl)-undecan-6-ol and a pharmaceutically acceptable salt thereof to treat the condition.
  • FIG. 1 shows hepatic triglyceride (TG) content of C57BL/6N male mice fed either a normal chow diet (NC); high-fat diet (HFD); high-fat diet+Compound A; or high-fat diet+Compound B, as explained in Example 1.
  • NC normal chow diet
  • HFD high-fat diet
  • Compound A high-fat diet+Compound A
  • Compound B high-fat diet+Compound B
  • the invention provides methods of using carboxy-cyclopropyl undecanol compounds and pharmaceutically acceptable salts thereof to treat liver disease and other medical disorders associated with elevated lipid levels in the liver.
  • the invention also provides methods of using compositions containing such compounds and/or medical kits to treat medical disorders in a patient.
  • Particularly preferred embodiments provide methods of treating steatohepatitis, such as nonalcoholic steatohepatitis using the compound 1,11-bis-(1-carboxy-cyclopropyl)-undecan-6-ol or a pharmaceutically acceptable salt thereof.
  • the compound 1,11-bis-(1-carboxy-cyclopropyl)-undecan-6-ol has the following chemical formula (hereinafter designated “Compound A”):
  • the invention provides methods of using carboxy-cyclopropyl undecanol compounds and pharmaceutically acceptable salts thereof to treat liver disease and other medical disorders associated with elevated lipid levels in the liver.
  • Treatment methods include the use of carboxy-cyclopropyl undecanol compounds described herein as stand-alone therapeutic agents, and/or as part of a combination therapy with another therapeutic agent.
  • One aspect of the invention provides a method of treating a liver disorder selected from the group consisting of steatohepatitis, alcoholic liver disease, fatty liver, liver steatosis, liver cirrhosis, liver fibrosis, and acute fatty liver of pregnancy.
  • the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of 1,11-bis-(1-carboxy-cyclopropyl)-undecan-6-ol and a pharmaceutically acceptable salt thereof to treat the disorder.
  • the disorder is steatohepatitis.
  • the steatohepatitis is nonalcoholic steatohepatitis.
  • the steatohepatitis is nonalcoholic fatty liver disease.
  • the disorder is alcoholic liver disease.
  • the disorder is fatty liver.
  • the disorder is liver steatosis, liver cirrhosis, or liver fibrosis.
  • the disorder is acute fatty liver of pregnancy.
  • the compound is 1,11-bis-(1-carboxy-cyclopropyl)-undecan-6-ol.
  • the patient is an adult human.
  • Another aspect of the invention provides a method of treating a disorder selected from the group consisting of lipodystrophy, lysosomal acid lipase deficiency, and a glycogen storage disease.
  • the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of 1,11-bis-(1-carboxy-cyclopropyl)-undecan-6-ol and a pharmaceutically acceptable salt thereof to treat the disorder.
  • the compound is 1,11-bis-(1-carboxy-cyclopropyl)-undecan-6-ol.
  • the patient is an adult human.
  • Another aspect of the invention provides a method of treating a disorder selected from the group consisting of hepatitis C, an infection by human immunodeficiency virus, an alpha 1-antitrypsin deficiency, Bassen-Kornzweig syndrome, hypobetalipoproteinemia, Celiac disease, Wilson disease, and Weber-Christian syndrome.
  • the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of 1,11-bis-(1-carboxy-cyclopropyl)-undecan-6-ol and a pharmaceutically acceptable salt thereof to treat the disorder.
  • the disorder is hepatitis C. In certain other embodiments, the disorder is an infection by human immunodeficiency virus. In certain other embodiments, the disorder is an alpha 1-antitrypsin deficiency. In certain other embodiments, the disorder is Bassen-Kornzweig syndrome. In certain other embodiments, the disorder is hypobetalipoproteinemia. In certain other embodiments, the disorder is Celiac disease or Wilson disease. In certain other embodiments, the disorder is Weber-Christian syndrome.
  • the compound is 1,11-bis-(1-carboxy-cyclopropyl)-undecan-6-ol.
  • the patient is an adult human.
  • Another aspect of the invention provides a method of treating a condition selected from the group consisting of toxic liver injury, total parenteral nutrition, severe surgical weight loss, environmental toxicity, malnutrition, and starvation.
  • the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of 1,11-bis-(1-carboxy-cyclopropyl)-undecan-6-ol and a pharmaceutically acceptable salt thereof to treat the condition.
  • the condition is toxic liver injury. In certain embodiments, the condition is total parenteral nutrition or severe surgical weight loss. In certain embodiments, the condition is environmental toxicity. In certain embodiments, the condition is malnutrition or starvation.
  • the compound is 1,11-bis-(1-carboxy-cyclopropyl)-undecan-6-ol.
  • the patient is an adult human.
  • the description above describes multiple embodiments relating to methods of treating various diseases, disorders, and conditions using certain carboxy-cyclopropyl undecanol compounds or pharmaceutically acceptable salts thereof.
  • the patent application specifically contemplates all combinations of the embodiments.
  • the patent application contemplates treating nonalcoholic steatohepatitis by administering to a patient in need thereof a therapeutically effective amount of 1,11-bis-(1-carboxy-cyclopropyl)-undecan-6-ol to thereby treat nonalcoholic steatohepatitis.
  • Procedures for identifying patients suffering from one or more of the medical disorders described herein are described in the literature and/or can be determined by medical personnel according to routine medical procedures. For example, diagnostic methods based on identification of biomarkers have been described for predicting, diagnosing, or staging NAFLD. Certain reports indicate that those with NAFLD at risk for progression of hepatic steatosis to NASH can be identified based on unexplained increases to >2.5 times the upper limit of AST levels, ALT levels, or both, excessive body weight, type 2 diabetes, and unexplained hepatotnegaly.
  • markers include increased alkaline phosphatase, elevated ferritin levels, ALT concentrations exceeding AST levels, and unexplained increases in serum aminotransferase levels in overweight and obese individuals (Grattagliano et al., Can. Fam. Physician 2007, 53, 857-86).
  • biomarker levels can be used to predict those at risk of developing NAFLD or diagnose those with NAFLD
  • these marker assays can be supplemented with histological assessments (e.g., liver biopsies) or non-invasive imaging modalities.
  • Non-invasive imaging modalities known in the art for assessing NAFLD include, but are not limited to, magnetic resonance imaging (MRI), diffusion weighted MRI, and ultrasound elastography or MRI elastography. Such non-invasive imaging modalities provide a useful and painless alternative for determining the presence of NAFLD and staging NAFLD progression.
  • Metabolic syndrome is a collection of risk factors estimated to affect over 50 million Americans. There is currently a lack of well-accepted criteria for diagnosing metabolic syndrome; however, those that are affected typically exhibit abdominal obesity, atherogenic dislipidemia, elevated blood pressure, insulin resistance or glucose intolerance, prothrombotic state and a proinflammatory state.
  • the invention is directed to using carboxy-cyclopropyl undecanol compounds or pharmaceutically acceptable salts thereof to treat liver disease and other medical disorders associated with elevated lipid levels in the liver, wherein the mammal in need of such treatment has or is at risk of developing metabolic syndrome.
  • Patients with metabolic syndrome can be identified via a number of established criteria. Exemplary criteria currently used to diagnose metabolic syndrome can be found in, for example, the World Health Organization (criteria established in 1999) (World Health Organization (WHO). Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO consultation, 1999), the Adult Treatment Panel III Report 2001 (Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults.
  • the invention embraces combination therapy, which includes the administration of a carboxy-cyclopropyl undecanol compound or pharmaceutically acceptable salt thereof (such as Compound A) and a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents.
  • the beneficial effect of the combination may include pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
  • Contemplated agents that may be co-administered with a carboxy-cyclopropyl undecanol compound or pharmaceutically acceptable salt thereof in the present methods include antiviral agents (e.g., to treat an underlying hepatitis C infection causing liver disease in the patient), anticancer agents (e.g., to treat hepatocellular carcinoma or other cancer causing liver disease or fatty liver), antioxidants, medications that decrease insulin resistance, or medications that improve lipid metabolism (e.g., treatments for hyperlipidemia).
  • antiviral agents e.g., to treat an underlying hepatitis C infection causing liver disease in the patient
  • anticancer agents e.g., to treat hepatocellular carcinoma or other cancer causing liver disease or fatty liver
  • antioxidants e.g., to treat hepatocellular carcinoma or other cancer causing liver disease or fatty liver
  • medications that decrease insulin resistance e.g., treatments for hyperlipidemia.
  • the invention provides pharmaceutical compositions comprising a carboxy-cyclopropyl undecanol compound or pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions preferably comprise a therapeutically-effective amount of one or more of the carboxy-cyclopropyl undecanol compounds or pharmaceutically acceptable salts thereof described herein, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those targeted for buccal, sublingual, and/or systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration by, for example, subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions),
  • terapéuticaally-effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the sub-population of cells is in an animal. In certain embodiments, the sub-population of cells is in a human.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, or most preferably from about 10 percent to about 30 percent.
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxa
  • pharmaceutically-acceptable carriers such as sodium citrate or dicalcium phosphate
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg.
  • the effective amount may be less than when the agent is used alone.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.
  • kits for treating a disorder comprises: i) instructions for treating a liver disorder, such as nonalcoholic steatohepatitis; and ii) a carboxy-cyclopropyl undecanol compound or pharmaceutically acceptable salt thereof, such as Compound A.
  • the kit may comprise one or more unit dosage forms containing an amount of a carboxy-cyclopropyl undecanol compound or pharmaceutically acceptable salt thereof, that is effective for treating said liver disorder.
  • Modulating or “modulate” in the context of the present invention means increasing, decreasing, or otherwise altering, adjusting, varying, changing, enhancing or inhibiting a biological event.
  • a “modulator” may be a compound, agent or drug that increases, decreases, alters, adjusts, varies, changes, enhances, or inhibits a biological event.
  • Liver disorder refers generally to diseases, disorders, and conditions affecting the liver, and may have a wide range of severity encompassing, for example, simple accumulation of fat in the hepatocytes (steatosis), macrovescicular steatosis, periportal and lobular inflammation (steatohepatitis), cirrhosis, fibrosis, liver cancers, and liver failure.
  • fatty liver disease which is also called fatty liver, refers to a disease leading to liver injury caused by abnormal fat accumulation in liver cells. FLD may arise from a number of sources, including excessive alcohol consumption and metabolic disorders, such as those associated with insulin resistance, obesity, and hypertension.
  • non-alcoholic fatty liver disease is intended to refer to the spectrum of disorders resulting from an accumulation of fat in liver cells in individuals with no history of excessive alcohol consumption.
  • NAFLD refers to hepatic steatosis.
  • drug-induced liver disease or “toxic liver injury” is used to describe those instances in which an active agent has caused injury to the liver.
  • alcoholic liver disease also called alcoholic liver injury
  • diseases such as alcoholic simple fatty liver, alcoholic steatohepatitis (ASH), alcoholic hepatic fibrosis, alcoholic cirrhosis and the like.
  • ASH alcoholic steatohepatitis
  • alcoholic hepatic fibrosis alcoholic cirrhosis and the like.
  • alcoholic steatohepatitis is also called alcoholic fatty hepatitis and includes alcoholic hepatic fibrosis.
  • Acute fatty liver conditions can also arise during pregnancy and can be life-threatening. These conditions are referred to herein as “fatty liver of pregnancy”.
  • the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers.
  • stereoisomers when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom.
  • the present invention encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers.
  • Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
  • Stereoisomeric mixtures can also be resolved into their component stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
  • the invention also embraces isotopically labeled compounds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • the terms “subject” and “patient” refer to organisms to be treated by the methods of the present invention. Such organisms are preferably mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and more preferably humans.
  • the term “effective amount” refers to the amount of a compound (e.g., a compound of the present invention) sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
  • the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
  • composition refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents.
  • the compositions also can include stabilizers and preservatives.
  • stabilizers and adjuvants see, e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. [1975].
  • the term “pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention which, upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof.
  • salts of the compounds of the present invention may be derived from inorganic or organic acids and bases.
  • acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and compounds of formula NW 4 + , wherein W is C 1-4 alkyl, and the like.
  • alkali metal e.g., sodium
  • alkaline earth metal e.g., magnesium
  • W is C 1-4 alkyl
  • salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate,
  • salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
  • salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.
  • mice C57BL/6N male mice were obtained from Charles River Laboratories (Montreal, QC, Canada) at 11 weeks of age and singly housed on alpha-dri paper bedding on a normal 12 hour, 6 am-6 pm light-dark cycle.
  • 7 mice were fed D12492 high fat diets (HFD) containing 60% kcal fat while 9 mice were fed D12450K normal chow diet (NC) for 1 week with free access to water.
  • HFD high fat diets
  • NC normal chow diet
  • Mice that had been fed D12492 were allocated into three equally distributed treatment arms of 9 mice each at 12 weeks of age based on 4-hour fasted blood glucose and body weight.
  • mice were euthanized and a random lobe of liver was flash frozen in liquid nitrogen for subsequent hepatic lipid analysis.
  • Approximately 100 mg of flash frozen liver was homogenized in a glass screw-top vial in 0.50 mL of 150 mM sodium chloride (NaCl)/5 mM 3-(N-morpholino) propanesulfonic acid (MOPS)/1 mM EDTA/0.01% phenylmethylsulfonyl fluoride (PMSF) and extracted twice with 2:1 dichloromethane:methanol (CH 2 Cl 2 :MeOH). The combined bottom organic phase was concentrated to dryness at 37° C.
  • NaCl sodium chloride
  • MOPS 3-(N-morpholino) propanesulfonic acid
  • PMSF phenylmethylsulfonyl fluoride
  • Results of the experiment show that Compound A reduces hepatic triglyceride in the mice test subjects.
  • Compound A was found to be more efficacious than Compound B (1.1% w/w). Food consumption was similar across the HFD groups.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Obesity (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US15/125,401 2014-03-20 2015-03-20 Carboxy-cyclopropyl undecanol compounds for treatment of liver disease and other medical disorders Abandoned US20170209402A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US15/125,401 US20170209402A1 (en) 2014-03-20 2015-03-20 Carboxy-cyclopropyl undecanol compounds for treatment of liver disease and other medical disorders

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201461968082P 2014-03-20 2014-03-20
PCT/US2015/021677 WO2015143276A1 (fr) 2014-03-20 2015-03-20 Composés carboxy-cyclopropyl undécanol pour le traitement de maladie hépatique et d'autres troubles médicaux
US15/125,401 US20170209402A1 (en) 2014-03-20 2015-03-20 Carboxy-cyclopropyl undecanol compounds for treatment of liver disease and other medical disorders

Publications (1)

Publication Number Publication Date
US20170209402A1 true US20170209402A1 (en) 2017-07-27

Family

ID=54145365

Family Applications (1)

Application Number Title Priority Date Filing Date
US15/125,401 Abandoned US20170209402A1 (en) 2014-03-20 2015-03-20 Carboxy-cyclopropyl undecanol compounds for treatment of liver disease and other medical disorders

Country Status (6)

Country Link
US (1) US20170209402A1 (fr)
EP (1) EP3119388B1 (fr)
JP (1) JP6633609B2 (fr)
AU (1) AU2015231076B2 (fr)
CA (1) CA2942100A1 (fr)
WO (1) WO2015143276A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3370713A4 (fr) * 2015-11-06 2019-10-23 Gemphire Therapeutics Inc. Traitement de la dyslipidémie mixte
WO2019179494A1 (fr) * 2018-03-23 2019-09-26 深圳市塔吉瑞生物医药有限公司 Composé d'acide pentadécanedioïque substitué, composition pharmaceutique et utilisation associée
CN112675159A (zh) * 2021-01-12 2021-04-20 杭州师范大学 L-苹果酸在制备防治肝脏缺血再灌注损伤药物中的应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK2404890T3 (en) * 2003-01-23 2017-10-16 Esperion Therapeutics Inc Hydroxyl compounds and compositions for controlling cholesterol and related uses
AU2011305610A1 (en) * 2010-09-20 2013-03-14 Kareus Therapeutics, Sa Methods and compositions for treatment of diabetes and dyslipidemia

Also Published As

Publication number Publication date
EP3119388B1 (fr) 2020-06-17
AU2015231076B2 (en) 2020-05-21
EP3119388A4 (fr) 2017-11-22
EP3119388A1 (fr) 2017-01-25
AU2015231076A1 (en) 2016-09-22
WO2015143276A1 (fr) 2015-09-24
CA2942100A1 (fr) 2015-09-24
JP2017509701A (ja) 2017-04-06
JP6633609B2 (ja) 2020-01-22

Similar Documents

Publication Publication Date Title
US20220133738A1 (en) Genotype and dose-dependent response to an asbti in patients with bile salt export pump deficiency
CA3079259A1 (fr) Ganaxolone destinee a etre utilisee dans le traitement de troubles epileptiques genetiques
TW201735924A (zh) 使用fxr促效劑之方法
KR102412997B1 (ko) 특정 환자 집단에서 신경퇴행성 장애를 치료하는 방법
CN116726178A (zh) sGC刺激剂在非酒精性脂肪性肝炎（NASH）治疗中的应用
EP3119388B1 (fr) Composés carboxy-cyclopropyl undécanol pour le traitement de maladie hépatique et d'autres troubles médicaux
US11793774B2 (en) Chiral beta-hydroxyethylamines and their use in the treatment of hyperglycemia
KR20150020160A (ko) 과민성 방광의 치료를 위한 무스카린 수용체 길항제 및 베타―3 아드레날린 수용체 작용제의 조합물
DK2440049T3 (en) GENOTYPE-SPECIFIC PROCEDURES FOR TREATING HUMAN INDIVIDUALS USING 4-METHYLPYRAZOLE
AU2017317575B2 (en) Treatment of nonalcoholic fatty liver disease
WO2022140279A1 (fr) Modulateurs synergiques de détoxication d'alpha-dicarbonyle et leur utilisation pour induire une perte de poids et traitement de pathologies diabétiques
WO2022024062A1 (fr) Procédés de réduction de la concentration en glycosphingolipides dans le tissu cérébral et procédés de traitement de maladies neurodégénératives impliquant ces derniers
JP2023529311A (ja) Ｃｆｔｒ関連疾患および障害を治療する方法
TW202333724A (zh) 以迴腸膽酸轉運蛋白(ibat)抑制劑治療以增加無事件存活期(efs)
WO2024108035A1 (fr) Compositions et méthodes de traitement du syndrome de prader-willi
CN118019540A (zh) 用于治疗多发性硬化的lou064
WO2020094592A1 (fr) Composés pour le traitement de symptômes négatifs et de déficiences cognitives

Legal Events

Date Code Title Description
AS Assignment

Owner name: ESPERION THERAPEUTICS, INC., MICHIGAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HANSELMAN, JEFFREY C.;SRIVASTAVA, RAI AJIT K.;NEWTON, ROGER S.;SIGNING DATES FROM 20150708 TO 20150918;REEL/FRAME:041982/0546

Owner name: ESPERION THERAPEUTICS, INC., MICHIGAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HANSELMAN, JEFFREY C.;SRIVASTAVA, RAI AJIT K.;NEWTON, ROGER S.;SIGNING DATES FROM 20150708 TO 20150918;REEL/FRAME:041982/0554

STPP Information on status: patent application and granting procedure in general

Free format text: FINAL REJECTION MAILED

STCV Information on status: appeal procedure

Free format text: NOTICE OF APPEAL FILED

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

STCB Information on status: application discontinuation

Free format text: EXPRESSLY ABANDONED -- DURING EXAMINATION